Natural killer T cells in intracerebral hemorrhage: phase-dependent immune responses and therapeutic implications

Intracerebral hemorrhage (ICH) is the most lethal subtype of stroke, yet effective disease-modifying therapies remain limited. Beyond the primary mechanical insult, dysregulated neuroinflammation is thought to be a major contributor to hematoma expansion, perihematomal edema, and secondary neuronal injury. Natural killer T (NKT) cells, a specialized population of lipid-reactive lymphocytes linking innate and adaptive immunity, have emerged as potentially relevant immunoregulatory contributors to the post-hemorrhagic response.

This review summarizes current experimental evidence, together with the still limited clinical data, regarding the biology of NKT cells in ICH, including their development, subset heterogeneity (type I invariant, type II, and regulatory NKT-like programs), and activation through CD1d-restricted lipid antigens and cytokine-driven pathways. Available evidence supports a phase-dependent working model of NKT-cell function in ICH. In the acute stage, type I iNKT-associated responses may amplify neuroinflammation through IFN-γ- and TNF-α-related signaling, thereby contributing to myeloid activation, blood-brain barrier (BBB) dysfunction, and neutrophil recruitment. In later stages, regulatory NKT-associated programs, including type II NKT- or NKT10-like responses, may become increasingly linked to IL-4-, IL-13-, and IL-10-related pathways that support pro-resolving myeloid phenotypes, hematoma clearance, and tissue repair. In addition, NKT cells may influence broader immune networks, including T-cell responses and, more speculatively, B-cell-associated pathways. We also discuss emerging therapeutic strategies targeting NKT-cell biology, including α-GalCer-based ligands, anti-CD1d/TCR approaches, sphingosine-1-phosphate (S1P) receptor modulators, and PPAR-γ agonists, while emphasizing the importance of treatment timing, delivery, and subset specificity.

Current evidence suggests that NKT cells may exert both detrimental and beneficial effects during ICH progression, with their impact varying according to disease stage and microenvironmental context. Their rapid responsiveness and functional plasticity make them promising, though still incompletely validated, targets for phase-tailored immunomodulation. Future progress will depend on high-resolution profiling to better define therapeutic windows, clarify subset-specific functions, and support the development of interventions that more precisely balance inflammatory control with tissue repair.